AT202147B - Process for the production of new piperazine derivatives and their salts - Google Patents

Description

  

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  Process for the production of new piperazine derivatives and their salts
The present invention relates to a process for the preparation of new piperazine derivatives of the general formula:
 EMI1.1
 in which the Rj radicals are identical or different alkyl radicals having 1-8 carbon atoms and n is a number from 0 to 10, preferably 0 to 6.



  The invention also relates to the preparation of the salts of the aforementioned piperazine derivatives with therapeutically useful acids.



   Piperazine derivatives disubstituted in the 1,4-position by alkyl radicals are already known. However, the piperazine compounds described in the literature are either substituted symmetrically in the 1,4-position by unbranched aralkyl radicals, as is the case, for example, with 1,4-dibenzylpiperazine (CA [1949] p. 310), or they are asymmetrical by an aryl -branched and one unbranched Aral-
 EMI1.2
 (Swiss Patent No. 299879). From a physiological point of view, it is noteworthy that these known piperazine compounds have predominantly antihistaminic and antispasmodic properties.



   It has now been found that the piperazine compounds of the above general formula, which are symmetrically substituted in the 1,4-position by alkyl-branched aralkyl radicals, and their salts with therapeutically useful acids have a pronounced central depressant, narcosis-potentiating and peripheral vasodilating effect. These surprising properties could not be foreseen and are therapeutically valuable.



   The compounds of the claimed type not yet described in the literature can be prepared by the methods customary and known for this group of compounds.



   The new compounds can be prepared by reacting piperazine with an aralkyl halide of the general formula:
 EMI1.3
 wherein Hal represents a halogen atom and R1 and n have the meaning given, obtained in the presence of metal hydroxides, carbonates or bicarbonates or organic bases. You can also use piperazine itself as a condensing agent by using it in excess for reaction with the alkyl halide.



   The piperazines disubstituted according to the invention in the 1,4-position by secondary aralkyl radicals are light-colored oils which can usually be distilled without decomposition in a vacuum below 1 Torr.



  They form well-crystallized salts with therapeutically useful acids such as hydrohalic acids, sulfuric and nitric acid and organic acids such as formic and acetic acid.
Due to the presence of two asymmetric carbon atoms, the claimed piperazines can occur in isomers. It has been found that the racemic compounds are formed in the reaction of primary amines with alkylene dihalides in the presence of alkali metal carbonates at temperatures not above 110.degree. The meso compounds are obtained from primary amines, alkylene dihalide and alkali metal hydroxide at temperatures above 130.degree. Racemate and meso compound can easily be separated via their hydrobromide salts.

   The racemate hydrobromide is in hot methanol

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 easily, the meso-hydrobromide compound is insoluble in hot methanol.



   The piperazine compounds obtained according to the process show therapeutically valuable properties. The pharmacological investigation showed that these compounds exert strong central depressant and narcosis-potentiating effects on animals. Particularly noteworthy is the strong and long-lasting peripheral vasodilator effect, as a result of which these compounds represent valuable therapeutics for the treatment of peripheral circulatory disorders.



   The compounds prepared according to the invention are intended to be used as medicinal products.



   The present invention is illustrated by the following example.



   Example: A mixture of 37 g of oc-phenyl ethyl bromide and 38.4 g of piperazine hexahydrate is heated to 130-140 ° C. for 14 hours. After cooling, the reaction product is broken down in 250 cm3 of water with the addition of 2N NaOH until it reacts strongly alkaline. The oil which separates out is extracted by shaking with methylene chloride and, after the solution has been dried and the methylene chloride has been stripped off, the volatile components are removed in a vacuum of 5 to 6 millitorr. The distillation residue that solidifies is then dissolved in 130 cm of boiling methanol, 16 cm3 of aqueous hydrobromic acid (33%) are added and the crystals which precipitate out are suctioned off while hot.

   The di- (<x-methylbenzyl) piperazine dihydrobromide obtained in this way can be recrystallized from water and forms a white powder with a melting point above 330 C.

 

Claims (1)

PATENT CLAIM: Process for the preparation of new piperazine derivatives of the general formula: EMI2.1 in which the R1 radicals are identical or different alkyl radicals having 1-8 carbon atoms and n is a number from 0 to 10, preferably 0 to 6, and salts thereof, characterized in that piperazine with an aralkyl halide of the general Formula: EMI2.2 wherein Hal is a halogen atom and R1 and n are as defined above, in the presence of metal hydroxides, carbonates or bicarbonates or organic bases and the EMI2.3 therapeutically usable acids converted into their salts.